This invention relates to processes suitable for the large scale preparation of enantiomerically enriched chiral carboxylic acid derivatives. In particular, it relates to asymmetric hydrogenation of prochiral substrates, using a transition metal catalyst complex.
Asymmetric hydrogenation has been used to convert prochiral substrates having the partial formula Cxe2x95x90Cxe2x80x94Cxe2x80x94COOX to chiral compounds of the formula Cxe2x80x94Cxe2x80x94Cxe2x80x94COOX. See, for example, Yamamoto et al, J. Organometallic Chem., 1989, 370, 319, where the substrate is 3-phenyl-3-butenoic acid, and the catalyst is Rhxe2x80x94DIOP. X depends on the additive, including tertiary amines.
Examples of other substrates in such a reaction have generally had a carboxylate function at at least one chiral centre. For example, itaconic acid derivatives have been used.
Enantiomerically enriched 2-substituted succinic acids (see formulae 2a and 2b, below) have recently attracted interest as useful chiral building blocks and pepidomimetics in the design of pharmaceuticals, flavours and fragrances, and agrochemicals with improved properties. For example, the utility of 2-substituted acid derivatives has been amply demonstrated through the synthesis of a range of new potent orally bioavailable drugs [J. T. Talley et al., in Catalysis of Organic Reactions, J. R. Kosak, T. A. Johnson (eds.) Marcel Dekker, Inc. (1994) Chapter 6; and H. Jendralla, Synthesis (1994) 494].
Chiral succinates can be prepared simply (e.g., via Stobbe condensation) from unsubstituted succinic esters and aldehydes or ketones, followed by asymmetric hydrogenation of the intermediate xcex2-substituted itaconate derivatives. For example, itaconic acid or its sodium salt, can be enantioselectively hydrogenated to 2-methylsuccinic acid with rhodium catalysts bearing the chiral ligand N-acyl-3,3xe2x80x2-bis(diphenylphosphino)pyrrolidine (BPPM) in up to 92% enantiomeric excess (ee) [I. Ojima et al., Chem. Lett., 1978, 567; I. Ojima et al., Chem. Lett., 1978, 1145; K. Achiwa, Tetrahedron Lett., 1978, 1475]. A rhodium catalyst bearing the chiral diphosphine DIPAMP affords 2-methylsuccinate in up to 88% ee [W. C. Christofel, B. D. Vineyard, J. Am. Chem. Soc. 1979, 101, 4406; and U.S. Pat. No. 4,939,288]. Similar results have been obtained with a ruthenium catalyst containing the chiral diphosphine ligand BINAP [H. Kawano et al., Tetrahedron Lett., 1987, 28, 1905]. Rhodium catalysts bearing modified DIOP ligands provide 2-methylsuccinic acid derivatives with variable enantioselectivities, between 7 and 91% ee. In these latter reactions, the ee value is very dependent on the rhodium catalyst precursor and whether the free acid or the ester is used [T. Morimoto et al., Tetrahedron Lett., 1989, 30, 735]. Better results have been reported with a neutral rhodium catalyst of the chiral diphosphine 2,2xe2x80x2-bis(dicyclohexylphosphino)-6,6xe2x80x2-dimethyl-1,1xe2x80x2-biphenyl (BICHEP), whereby dimethylitaconate was hydrogenated in 99% ee [T. Chiba et al., Tetrahedron Lett., 1991, 32, 4745].
In contrast to the success achieved with unsubstituted itaconate derivatives, asymmetric hydrogenation of xcex2-substituted itaconic acid derivatives has been more challenging; relatively few reports of high enantioselectivity (over 90% ee) have appeared. No enantioselectivities above 90% ee have been reported for xcex2-alkyl-substituted itaconates.
Itaconate derivatives that possess two substituents in the xcex2-position (xcex2,xcex2-disubstituted itaconates of formula 1 where R3,R4xe2x89xa0H) have thus far proven impossible to hydrogenate with high enantioselectivities and high rates. The only reported example of this type revealed that dimethyl xcex2,xcex2-dimethylitaconate may be hydrogenated with a Rh-TRAP catalyst system with the highest enantioselectivities being 78% ee [R. Kuwano et al, Tetrahedron: Asymmetry, 1995, 6, 2521].
It should be noted that enantiomerically pure compounds are required for many applications in, for example, the pharmaceutical industry. Consequently, providing enantiomeric purity is the ultimate objective of an asymmetric process, and achieving high enantioselectivity in a transformation of the type described herein is crucial from a process standpoint. 90% ee is often selected as a lower acceptable limit because compounds often may be purified to enantiomeric purity through recrystallisation when the initial value is above 90% ee. Enantiomeric excesses lower than 90% ee become increasingly more difficult to purify.
The present invention is based on the discovery that an efficient and high-yielding preparation of an enantiomerically enriched chiral carboxylic acid by asymmetric hydrogenation, e.g. in the presence of a transition metal complex of a chiral phosphine, is facilitated by use of particular salt forms of the hydrogenation substrate. Examples of such substrates are itaconates, which are referred to herein by way of example only. More generally, the products of the invention have the partial formula Cxe2x80x94Cxe2x80x94Cxe2x80x94COOX, X being a cation. The corresponding acid will usually be obtained, on work-up.
The use of salt forms can have a number of advantages. Firstly, formation and isolation of a salt form, using a substantially stoichiometric amount of base, may provide a convenient means of effecting substrate purification prior to hydrogenation, should this be required. Secondly, at a given molar ratio of substrate to catalyst (S/C ratio) and reaction time, a higher substrate conversion and/or higher enantioselectivity can be achieved. Thirdly, high reaction rates allow reactions to be performed at low temperatures, e.g. 0xc2x0 C., whereby higher product enantiopurity is observed.
The substrate for hydrogenation is prochiral, i.e. it is asymmetrically substituted about the Cxe2x95x90C bond. One substituent is xe2x80x94Cxe2x80x94COOX, and the combination of chain length and carboxylate anion provides the ability of the substrate to coordinate a metal catalyst. There may be none or any substituents on the same C atom of the Cxe2x95x90C bond as xe2x80x94Cxe2x80x94COOX, provided that they do not interfere with the reaction. For example, in the hydrogenation of a substrate of the formula R3R4Cxe2x95x90CR1xe2x80x94CH2xe2x80x94 COOR2, R1, R3 and R4 are each essentially spectators, although R3 and R4 are not both hydrogen. A characteristic of this invention is that no carboxylate function other than COOX is necessary.
Such substrates are known or may be prepared by methods known to those skilled in the art. In the particular case when R1 is COOR2, COOalkyl or COOaryl, both xcex2-substituted and xcex2,xcex2-disubstituted derivatives may be prepared. Itaconates for use as substrates are also described in PCT/GB98/03784 and U.S. patent application Ser. No. 09/213,745, filed Dec. 17, 1998, the contents of which are incorporated herein by reference.
Suitable substrates for the hydrogenation process outlined above are of the general structure 7 or 8 (for the preparation of products 2) 
or a mixture thereof, wherein R1, R3 and R4 can be independently H or an organic group of up to 30 C atoms or R3 and R4 are joined to form a ring, provided that at least one of R3 and R4 is not H. In one embodiment, the invention provides an improved procedure in the case where one of R3 and R4 is H; typically, the other is C1-20 alkyl or aralkyl. By way of example, the fact that xcex2,xcex2-disubstituted itaconates can be effectively hydrogenated in this process means also that R3 and R4 may each be an organic group of up to 30 C atoms, e.g. C1-20 alkyl or aralkyl, and preferably the same, or may be linked to form a ring, e.g. a saturated carbocyclic ring. In this case, R1 may be COOC1-10 alkyl, COO aryl or COO aralkyl.
X may represent a metal, e.g. alkali metal, or other cation. The metal salt may be preformed or formed in situ, by introducing a strong base such as a metal alkoxide, e.g. NaOMe.
Alternatively, the salt may be formed with, for example, a counterion YH+ such as that derived from an amine Y or a phosphine Y. Primary C1-10 alkylamines and cycloalkylamines are preferred, in particular, tert-butylamine. Tertiary amines such as triethylamine may also be used.
Especially when an amine or phosphine salt is used, it is usually isolated prior to use in the process, but alternatively may be generated in situ. Isolation of the precursor salt can be advantageous as a means of effecting substrate purification, usually by crystallisation, e.g. to remove any regioisomeric contaminants. However, this step is not always necessary, especially when the Stobbe condensation is carried out under carefully controlled conditions where regioisomeric contaminants are not formed, e.g. at a temperature of around 5xc2x0 C. rather than at normal room temperature.
Temperature effects may also be noted in the process of the present invention, with a lowering of reaction temperature resulting in improved enantioselectivities for certain substrates, e.g. when R3/R4 is a cyclic group, or if the precursor is an amine or phosphine salt. Especially in such cases, the reaction temperature may be less than 10xc2x0 C., and is preferably xe2x88x9225 to +5xc2x0 C.
Catalysts that are suitable for the asymmetric hydrogenation process comprise a transition metal complexed to an appropriate chiral phosphine ligand. Preferably, the ligand is a monophosphine or diphosphine ligand which may be used in either enantiomeric form. The preferred transition metal is rhodium; others that may be used include ruthenium and iridium.
Preferred phosphines are those incorporating an appropriately substituted phosphorus heterocycle of general structure 10, where n is zero or an integer 1 to 6, and where the carbocyclic framework of 10 is substituted with one or more R substituents such that the structure 10 is a chiral entity, and where the R substituent is an organic group of up to 20 C atoms, typically a C1-10 linear or branched hydrocarbon substituent, but which also may contain heteroatoms. In the case where more than one R substituent is present in the structure 10, these R substituents may be the same or different, and may be joined to form ring systems fused with the parent carbocyclic framework illustrated for 10. Monophosphines containing the phosphorus heterocyclic unit 10 take the general structure 11, where Rxe2x80x2 is an organic group of up to 20 C atoms. Alternatively, two phosphorus heterocycles of structure 10 may be tethered with a linking unit to form a diphosphine of general structure 12, where the linking unit is an organic group of up to 30 C atoms, linear, branched or cyclic, hydrocarbon or heteroatomic in nature. 
Examples of these ligands encompass 2,4-disubstituted phosphetanes 13, e.g. as disclosed in WO-A-9802445, as well as the DuPHO [U.S. Pat. No. 5,171,892] and BPE [U.S. Pat. No. 5,008,547] series of bisphospholanes, 14 and 15, respectively. The latter ligands constitute the most preferred class of disphosphines for the asymmetric hydrogenation process described herein. 
The possession of a series of homologous ligands of types 11-15 which are substituted with a range of different R groups is crucial for success in asymmetric hydrogenations since it is difficult to predict which catalyst will hydrogenate a particular substrate type with high selectivity. For a given substrate, enantioselectivities may be dependent upon the nature of the R-substituent attached to the carbocyclic ring of the DuPHOS, BPE or other ligand (as can be seen from Table 1, below). Typically, a range of ligand-metal complexes may be screened, in order to identify the optimum catalyst for a given transformation, although such screening is readily done by one of ordinary skill in the art, if necessary with reference to the guidance provided herein. The appropriate complex may change, from substrate type to substrate type: rhodium complexes containing certain DuPHOS and BPE ligands have been shown to hydrogenate several types of olefinic substrates, such as enamides, with very high enantioselectivity [Burk et al., J. Am. Chem. Soc., 1993, 115, 10125], while other substrates such as xcex1,xcex2-unsaturated carboxylic acids and allylic alcohols are reduced with only very low selectivities. For example, both xcex2-substituted and xcex2,xcex2-disubstituted xcex1-enamide esters may be hydrogenated to xcex1-amino acid derivatives with high enantioselectivity using certain DuPHOS and BPE-rhodium catalysts [Burk et al., J. Am. Chem. Soc., 1995, 117, 9375]. Furthermore, xcex2-substituted xcex1-arylenamides may be hydrogenated to xcex1-arylalkylamine derivatives with high enantioselectivities [Burk et al., J. Am. Chem. Soc., 1996, 118, 5142], yet xcex2,xcex2-disubstituted xcex1-arylenamides are hydrogenated with the same catalysts with very low enantioselectivity (0-5% ee).
The value of using a salt as the substrate is evident in the case where the hydrogenation substrate is a xcex2,xcex2-disubstituted itaconate derivative, for example wherein R3xe2x95x90R4=methyl. Otherwise, it may be that high substrate conversion is difficult to achieve at acceptable S/C ratios (typically  greater than 200:1). See, for example, Examples 1 and 2. In the former, hydrogenation of the tert-butylamine salt of 2-isopropylidenesuccinic acid 1-methyl ester, catalysed by a rhodium(I) complex of (R,R)-methyl BPE, with S/C=500:1, was conducted at 0xc2x0 C. using methanol as solvent. This gave complete substrate conversion after 20 hours, to afford after said cracking (R)-2-isopropylsuccinic acid 1-methyl ester in 95% ee. Enrichment of the salt to at least 99% ee could then be simply achieved by reslurrying in fresh solvent and then filtering. In Example 2, reaction of the free acid of of 2-isopropylidenesuccinic acid 1-methyl ester under similar conditions, with a higher catalyst loading (S/C=300:1), gave only 33% substrate conversion, with (R)-2-isopropylsuccinic acid 1-methyl ester produced in 88% ee.
Overall, the present invention provides a straightforward process for the synthesis of valuable, highly enantiomerically enriched chiral carboxylic acid derivatives, starting from readily available, inexpensive starting materials.
The following Examples illustrate the invention, except Example 2 which is comparative.
TBME=tert-butyl methyl ether
GC=gas chromatographic analysis